The recent identification and development of small molecules that activate p53 open new possibilities for colon cancer treatment and prevention where the mutational inactivation of p53 is typically a late event in the adenoma-carcinoma sequence. Our preliminary data indicate that p53 in AOM-induced mouse colon tumors is primed for activation by the recently developed Mdm2 inhibitor Nultin-3, making these tumors hypersentive to this compound. We propose that stimulating p53 activity at selected stages of carcinogenesis will serve to suppress colon cancer development. To test this hypothesis, we will determine if the Mdm2 inhibitor Nutlin-3 can induce stasis or regression of colon tumors in the mouse AOM model (Aim 1). We will also determine whether Nutlin-3 can selectively activate p53 and apoptosis in human colon adenomas and mouse aberrant crypt foci (using an ex vivo culture format;Aim 2). Finally, we will determine whether the expression levels of the epigenetically regulated ARF gene sensitizes colon cancer and adenoma cells to Nutlin-3 or dietary agents that affect the p53 pathway (Aim 3). The long term goals of these exploratory studies are to: 1) establish p53/Mdm2 as a target for colon cancer prevention agents, 2) determine the stage of carcinogenesis when Mdm2 inhibitors are most effective and 3) determine the contribution of ARF to sensitizing transformed cells to agents that activate p53. PUBLIC HEALTH RELEVANCE:Colon polypectomy is an important tool for colon cancer prevention. However, limitations to this approach include the incomplete removal of sessile polyps and the missed detection of small adenomas. Our goal is to develop safe and effective pharmacological or dietary agents, to be used in conjunction with present treatment practices, to suppress the risk of colon cancer development in high risk patients.